Schematic representation of the negative feedback system regulating TDP-43 function through FUS, hnRNP K, and hnRNP A1. (A) The binding consensus of FUS is widely present in TARDBP exon 6, including the 3′ UTR of MP20. FUS may inhibit the translation of MP20 by interacting with TARDBP RNA. (B) HnRNP K promotes splicing to MP20 while inhibiting FL, leading to the induction of MP20 expression with dominant-negative activity. WT FUS inhibits MP20 expression via multifaceted mechanism: by inhibiting hnRNP K expression and directly suppressing the posttranscriptional process of MP20. FUS seems to promote the increase of MP20 RNA levels, although its exact mechanism remains unclear. (C) The ALS-causing mutant FUS (P525L) not only increases MP20 RNA but also leads to the dysrepression of MP20 at each regulatory point, potentially affecting TDP-FL expression and function due to its aberrant dominant-negative activity. (D) Our study indicates a negative feedback mechanism in which hnRNP A1 is induced to counteract the effects of hnRNP K, which inhibits canonical TDP-43. These findings suggest that abnormalities in any of the RBPs involved in this regulatory system could result in dysfunction of TDP-43.